Lung fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins (ECM) in lung parenchyma. Globally, five million people are affected by lung fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of lung fibrosis on quality of life is severe. Lung fibrosis of unknown causes is known as idiopathic pulmonary fibrosis (IPF). Lung fibrosis also develops as a consequence of multiple causes, including radiotherapy and chemotherapy for lung neoplasms. Radiation-induced lung fibrosis is a major concern for radiotherapy for cancer patients. Therapy-induced fibrosis often limits the efficacy of the combination of chemotherapy and radiotherapy in numerous cancers. Currently, there are no effective non-surgical treatments for lung fibrosis. Hence there is an urgent need to develop therapeutic agents that prevent and ameliorate lung fibrosis. Accumulating evidence indicates that transforming growth factor-( (TGF-() plays an important role in its pathogenesis. Animal studies have shown that antagonizing TGF-( by treatment with TGF-( binding proteins appears to ameliorate lung fibrosis. Therefore synthetic TGF-( antagonists may serve as important therapeutic agents for lung fibrosis. We recently developed a class of synthetic TGF-( peptide antagonists (termed TGF-( peptantagonists) that block TGF-( binding to TGF-( receptors and antagonize TGF-( activity in cultured cells. Topical application of gel containing a TGF-( peptantagonist in standard animal skin injury models promotes wound healing and attenuates fibrosis. However, the use of TGF-( peptantagonists to treat lung fibrosis is limited by its poor solubility in aqueous solution at neutral pH. In recent studies, we have developed a novel pegylated TGF-( peptantagonist (termed PEG-TGF-( peptantagonist) which has excellent solubility in aqueous solution at neutral pH, potent antagonist activity as measured using cultured cells, and epithelial regeneration activity as determined using cyclophosphamide-induced bladder injury in rats. Intranasal administration of this PEG-TGF-( peptantagonist effectively prevents bleomycin-induced lung fibrosis in mice and attenuates established lung fibrosis as well. These results suggest that PEG-TGF-( peptantagonist may be a valuable therapeutic agent for prevention and treatment of lung fibrosis in humans. We hypothesize that our PEG-TGF-( peptantagonist is effective in ameliorating radiation-induced lung fibrosis. The major goal of this proposal is to test this hypothesis. The results from the proposed phase I studies should provide the basis for Phase II and clinical trials of this novel PEG-TGF-( peptantagonist. We predict that the clinical availability of our PEG-TGF-( peptantagonist will benefit millions of patients worldwide. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop novel TGF-( peptantagonist as a drug candidate for treating radiation-induced lung fibrosis which currently lacks effective treatments. The availability of such drug will benefit millions of patients worldwide.